Post-mitotic cells such as neurons must strictly regulate the pathway of apoptosis because these cells have limited regenerative potential and must survive for the lifetime of the organism. Understanding the molecular mechanisms of apoptosis, or programmed cell death, in neurons has enormous clinical significance due to the wide range of diseases which result from aberrant apoptotic regulation. For example, excessive activation of apoptosis is seen in neurodegenerative diseases and in neuronal loss after stroke. On the other hand, evasion of cell death is a hallmark of cancer. In order to better understand the pathogenesis of these diseases and to develop new therapeutics, it is crucial that we understand the molecular mechanisms by which neurons control apoptosis. The long-term objectives of this project are to understand the changes that occur in the regulation of apoptosis as neurons mature. Consistent with their need for long-term survival, we find that sympathetic neurons utilize an increasing number of mechanisms to prevent unwanted activation of the apoptotic pathway as they mature. The focus of this Competitive Supplement is on examining the importance of microRNAs (miRNAs) in this process. Using microarrays, we have identified changes in miRNA expression that correlate with changes in apoptotic restriction as sympathetic neurons mature. Our hypothesis is that these changes in miRNA expression have an important role in regulating the ability of these cells to survive cellular stresses. The specific aims of this proposal are two-fold: 1) to determine whether miR-29, which is upregulated during neuronal maturation, has a role in protecting cells from apoptotic stimuli, and 2) to determine if downregulation of the miRNA biogenesis machinery has a role in protecting mature neurons from apoptosis and if this is a result of miR-29 activity. PUBLIC HEALTH RELEVANCE: In many neurological diseases neurons inappropriately die, leading to subsequent disability or death of patients. The experiments proposed in this grant will help explain how neurons are able to survive for an organism's lifetime and may shed light on how this process malfunctions when cells die. This information could lead to new therapies for preventing unwanted neuronal death seen in neurodegenerative disease or as a result of stroke.